Optically active alkaloidal salts of etienoylpyruvic acids



United States Patent OPTICALLY ACTIVE ALKALOIDAL SALTS 63F ETIENQyLPYRUVIC ACIDS Glen E. Arth, Cranfhrd, and Robert M. Lultes, Nixon, 3., asslgnors to Merck & Co., Inc., Rahway, N. 1., a corporation of New Jersey No Drawing. Application September 17, 1952,

- Serial No. 310,136

11 Claims. (Cl. 2ti0--239.55)

This invention relates to novel processes for the rcsolution of racemic steroid compounds. More particularly, it is concerned with the preparation of the diastereoisomeric forms of dl-ll-lceto progesterone. Specifically, it is concerned with the preparation of novel optically active salts of A -3-ethylenedioxy-ll-keto-etienoylpyruvic acid,

optically active salts of A -3-ethylenedioxy-l l-keto-etienoylpyruvic acid. An additional object is to provide a process for the separation of the optically active salts of Lil-A 8-en1ylenedioxy-1l-lteto-etienoylpyruvic acid.

Other objects will be apparent from the detailed description of our invention hereinafter provided.

In accordance with the that a derivative of dl-ll-keto-progesterone, namely, d1- M-S-ethylenedioxy-ll-keto-etienoylpyruvic acid, reacts with optically active organic bases to form a mixture of the diastereoisomeric salts fractional crystallization. Thus, upon intimately contacting the racemic steroid compound with an optically active base in a suitable solvent medium, the acidic compound reacts With the base to form a mixture of the d and l salts which can be separated by fractional crystallization from suitable solvents.

Although any of the optically active organic bases can be used in the process of our invention, We have found that alkaloid bases such as strychnine, brucine, and

ephedrine are particularly valuable in carrying out our invention, since the resulting alkaloid salts of the d and 1 forms of A -3-ethy1enedioxy-ll-keto-etieuoylpyruvic acid are most readily separated by crystallization from common organii: solvents. Thus, the resolution of the racemic steroid is conveniently accomplished by fractionally crystallizing the strychnine salts of the racemic steroid. This separation can be effected for example by first preparing a crystalline mixture of the d and l strychnine salts by reacting A -3-ethylenedioxy-1l-keto-etienoylpyruvic acid with strychnine in hot acetone. Upon cooling, the acetone solution deposits a crystalline mixture consisting of the cl and l strychnine salts. This mixture of salts is then dissolved in hot ethyl acetate. When the resulting ethyl acetate solution is cooled, the strychnine salt of d-A -3-ethylenedioxy-1l-lteto-etienoylpyruvic acid precipitates and can be recovered from the solution by filtration. The strychnine salt of l-A -3-ethylenedioxy-1lketo-etienoylpyruvic acid can be recovered from the mother liquors by concentration of the mother liquors and recrystallization of the resulting residue. If desired, the d and 1 strychnine salts so obtained can be purified further by recrystallization from suitable solvents.

present invention, it is found which can be separated by d-A -3-ethylenedioxyl l-keto-etienoylpyruvic acid was sus- The d and l isomers of A -3sethylenedioxy-1l-ketoetienoylpyruvic acid are readily obtained by treating the separated salts with acid in aqueous solution, and extracting the resulting solution with a water immiscible solvent for the acidic steroid, such as ether.

The d and 1 forms of the etienoylpyruvic acid compound can then be converted to the d and 1 forms of M6- ethyienedioxy-l1,20-diketopregnene by alkaline hydrolysis. T .is is most conveniently accomplished by reacting the etienoylpyruvic acid compound with an alkali such as a dilute aqueous solution of an alkali metal oralkaline earth metal hydroxide, oxide, carbonate or bicarbonate. Thus, the hydrolysis is satisfactorily effected by reacting the acidic steroid compound with an aqueous solution of potassium bicarbonate at C. for about one-half hour.

The A -3-ethylenedioxy-11,20-diketopregnene can then be hydrolyzed to ll-lcetoprogesterone by treatment with acid. For example, the pregnene compound is hydrolyzed by reaction with a solution of perchloric acid in tetrahydrofuran at room temperature for two hours. After the hydrolysis is complete, the ll-keto progesterone is recovered by evaporating the reaction mixture to dryness under diminished pressure, extracting the residue with chloroform, and evaporating the chloroform extracts.

Thus, in accordance with the process of our invention, there is obtained. from dl-A -3-ethylenedioxy-1l-ketoetienoylpyruvic acid, two isomeric forms of ll-keto progesterone. the product prepared from natural sources which is described in Holy. Chem. Acta. vol. 23, 684 and vol. 26, 721.

The following examples illustrate methods of carrying out our invention.

EXAMPLE 1 A. Preparation of the strychm'ne salt of d-M-S-ethylenedioxyJJ-keto-etienoylpyruvic acid from dl-A -3 eZlzyZenedioxy-l 1 -keio-etienoylpyruvic acid A mixture of 0.4445 g. of dl-A -3-ethylenedioxy-11- keto-etienoylpyruvic acid and 0.3344 g. of strychnine was dissolved in 15 ml. boiling acetone. As the solution cooled it deposited crystals of the strychnine salt of d1- M-Bethylenedioxydl-keto-etienoylpyruvic acid, M. P. 168175 C. (doc). The yield was 742 mg. (96%) in three crops. This salt was dissolved i119 ml. of boiling ethyl acetate and allowed to cool, whereupon 300mg. of the strychnine salt of d-A -3-ethylenedi0xy-1l-ketoetienoylpyruvic acid crystallized out. This salt was collected on a filter, and after recrystallization from ethyl acetate had M. i. 215-2l6 C., [011 0i2 (1% solution in tetrahydroturan), and was identical in every respect. with a salt sample prepared from ll-keto progesterone obtained from natural sources.

B. d-A -3-ethylenerlioxy-11-ket0-etien0ylpyruvic acid Three hundred milligrams of the strychnine salt of pended in 25 ml. of water containing 2.0 g. of sodium dihydrogen phosphate and 0.1 ml. of 5 N sulfuric acid. This mixture was extracted 5 times with ether over a half hour period, each ether extract being washed with water. The combined ether extracts were evaporated in vacuo without application of heat to give 167 mg. of d A 3 ethylenedioxy 11 keto etienoylpyruvic acid, [al +46 +2 (1% solution in tetrahydrofuran).

keto-etienoylpyruvic acid in 10 ml. of 10% aqueous potassium bicarbonate was heated at 100 C. for /2 hour.

The crystalline precipitate which formed was extracted into ether. Evaporation of the ether gave 74 mg. of

crystalline residue which was adsorbed on 2 g. of acid The one form of this product is: identical with 3 washed alumina. El'ut'ion with 1:1 petroleum ether-ether and evaporation of the eluant gave A -3-ethylenedioxyr pregnene-11,20-dione, M. P. and mixed M. P. 175176.5 C., [a] +53 (1% solution in chloroform) after recrystallization from benzene-petroleum ether and from ethyl acetate-petroleum ether.

D. d-JI-keto progesterone A solution of 1.0 ml. of 3 N perchloric acid was added to a solution of 40 mg. d-A -3-ethylenedioxy-l1,20-diketo pregnene [M. P. 175-l76.5 C., [n] +53 (1% solution in chloroform)] in tetrahydrofuran. The reaction mixture was allowed to stand at room temperature for three and one half hours. The solvents were then removed in vacuo and the crude residue extracted with chloroform. The chloroform extract was dried over sodium sulfate and the solvent removed in vacuo. Recrystalization from ether yielded d-ll-keto progesterone, M. P. and mixed M. P. 178 C., infrared (solid), identical with an authentic sample of ll-keto progesterone obtained from natural sources.

The starting materi l, dl-A -3-ethylenedioxy-1l-ketoetienoylpyruvic acid used in the foregoing example can be prepared as described in copending application Serial No. 310,133, filed September 17, 1952.

EXAMPLE 2 Brzecine salt of d- A -3-ethylenedi0xy-1J-keto-etienoylpyruvic acid A mixture of 30 mg. of d-A -3-ethy1enedioxy-1l-ketoetienoylpyruvic acid and 30 mg. of anhydrous brucine was dissolved in boiling acetone. Upon cooling the solution,

45 mg. of the brucine salt of d-A -3-ethylenedioxy-l lketo-etienoylpyruvic acid crystallized out. After two recrystallizations from acetone, this salt had M. P. 175 180 C. (dec.) and [:11: 0i-2 (1% solution in tetrahydrofuran) EXAMPLE 3 S trychnine salt of d-A -3-ethylenedi0xy-11 -ket0-etien0ylpyruvic acid This was prepared in the same manner as the brucine salt, 30 mg. of d-A -3-ethylenedioxy-1l-keto-etienoylpyruvic acid and 23 mg. of strychnine yielding 32 mg. of the strychnine salt of d-A -3-ethylenedioxy-ll-keto-etienoylpyruvic acid. After recrystallization from ethyl acetate, this salt had M. P. 215-216" (1., and [M12 0:2 (1% solution in tetrahydrofuran).

EXAMPLE 4 Ephedrine salt of d-A -3-ethylenedioxy-1I-keto-etienoylpyruvic acid This was prepared and purified in the same manner as the brucine salt, 30 mg. of d-A -3-ethy1enedioxy-1l-ketoetienoylpyruvic acid and 12 mg. of anhydrous ephedrine yielding 25 mg. of ephedrine salt of A -3-ethylenedioxy- 1l-keto-etienoylpyruvic acid, M. P. 190-195 C.,

OHr-O wherein R represents a member from the group consisting of brucine, ephedrine and strychnine.

2. The brucine salt of A -3-ethylenedioxy-1l-ketoetienoylpyruvic acid having the structural formula (3112C OCOOH wherein B represents brucine.

3. The ephedrine salt of n -3rethylenedioxy-llwketoetienoylpyruvic acid having the structural formula wherein E represents ephedrine.

CHzCOCOOH wherein 5 represents strychnine.

5. The strychnine salt of d-A -3-ethylenedioxy-1l-ketoetienoylpyruvic acid having the structural formula C Hr-O CHLCOCOOH wherein S represents strychnine.

i with an alkaloid from the 6. The strychnine salt of l-M-3-ethylencdioxy-1l-ketoetienoylpyruvic acid having the structural formula wherein S represents strychnine.

7. The process which comprises reacting cll-A -3-ethylenedioXy-I l-keto-etienoylpyruvic acid having the struc tural formula group consisting of brucine, ephedrine and strychnine to form the corresponding alkaloid salts of the d and l isomeric forms of M6- ethylenedioxy-ll-keto-etienoylpyruvic acid, and separating said isomeric salts by fractional crystallization.

8. The process which comprises reacting dl-A -3-ethy1- enedioxy-ll-keto-etienoylpyruvic acid having the structural formula GHZOOGOOH C Hr-O with strychnine to form the strychnine salts of the d and l isomeric forms of A -3-ethylenedioxy-11-keto-etienoylpyruvic acid, and separating said isomeric salts by fractional crystallization.

9. The process which comprises reacting d1-A -3-ethylenedioxy-ll-keto-etienoylpyruvic acid having the structural formula (EH26 OC 0 OH 00 CHE-O Hs-O with strychnine to obtain'a mixture of the strychnine salts of the d and l isomers of A -3-ethylenedioxy ll-ketoetienoylpyruvic acid, dissolving said mixture of salts in ethyl acetate, and precipitating the alkaloid salt of the cl isomer fromthe resulting solution.

10. The process which comprises reacting a salt of an alkaloid from the group consisting of brucine, ephedrine, and strychnine and A -3-ethylenedi0xy-1l-keto-etienoylpyruvic acid With an acid, and recovering A -3-ethylenedioXy-ll-keto-etienoylpyruvic acid having the structural from the resulting reaction mixture.

11. The process which comprises reacting the strychnine salt of A -3-ethylenedioXy-l l-keto-etienoylpyruvic acid with an acid, and recovering A -3-ethylenedioxy-1l-ketoetienoylpyruvic acid having the structural formula 0 m0 0 0 0 DH Hz-O from the resulting reaction mixture.

No references cited. 

1. AN ALKALOID SALT OF $5-3-ETYHLENEDIOXY-11-KETOETIENOYLPYRUVIC ACID SELECTED FROM THE GROUP CONSISTING OF THE BRUCINE, EPHEDRINE AND STRYCHNINE SALTS OF $5-3ETHYLENEDIOXY-11-KETO-ETIENOYLPYRUVIC ACID HAVING THE STRUCTURAL FORMULA 